Synergistic effects of citicoline and silymarin nanomicelles in restraint stress-exposed mice

• Published in: Behavioural brain research 2024-04, Vol.464, p.114929, Article 114929
• Main Authors: Shayan, Elham, Maheri, Fatemeh, Aflaki, Fatemeh, Mousavi, Seyyedeh-Elaheh, Zarrindast, Mohammad-Reza, Fakhraei, Nahid, Rezayat Sorkhabadi, Seyyed-Mahdi, Shushtarian, Seyed-Mohammad-Masoud
• Format: Article
• Language: English
• Subjects: Animals; Antidepressive Agents - pharmacology; BDNF; Body Weight; Brain-Derived Neurotrophic Factor - metabolism; Citicoline; CREB; Cytidine Diphosphate Choline - metabolism; Cytidine Diphosphate Choline - pharmacology; Depression - metabolism; Hippocampus - metabolism; Mice; Restraint stress; Silymarin - metabolism; Silymarin - pharmacology; Silymarin nanomicelles; TNF-α; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0166-4328; 1872-7549; 1872-7549
• DOI: 10.1016/j.bbr.2024.114929

This study evaluated the effects of citicoline and silymarin nanomicelles (SMnm) in repeated restraint stress (RRS). Mice were exposed to RRS for four consecutive days, 2 hrs. daily. On day 5 of the study, SMnm (25 and 50 mg/kg, i.p.) and citicoline (25 and 75 mg/kg), and a combination of them (25 mg/kg, i.p.) were initiated. On day 18, anxiety-like behavior, behavioral despair, and exploratory behavior were evaluated. The prefrontal cortex (PFC) and the hippocampus were dissected measuring brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and tumor necrosis factor-alpha (TNF-α) through Western Blot and ELISA, respectively. In RR-exposed mice, anxiety-like behavior in the elevated plus maze (EPM) was enhanced by reductions in open arm time (OAT%) P < 0.001, and open arm entry (OAE%) P < 0.001. In the forced swimming test (FST), the immobility increased P < 0.001 while the swimming and climbing reduced P < 0.001. In the open field test (OFT), general motor activity was raised P < 0.05. Further, body weights reduced P < 0.001, and tissue BDNF and pCREB expressions decreased P < 0.001 while TNF-α increased P < 0.001. Conversely, SMnm, citicoline and their combination could reduce anxiety-like behavior P < 0.001. The combination group reduced the depressive-like behaviors P < 0.001. Moreover, body weights were restored P < 0.001. Besides, BDNF and pCREB expressions increased while TNF-α reduced, P < 0.001. The combination synergistically improved emotion-like behaviors, alleviating the inflammation and upregulating the hippocampal BDNF-mediated CREB signaling pathway.